JP2838529B2 - New optically active compounds - Google Patents

Abstract

(3S, 5S)-(-)-2,6-dimethyl-3,5-heptanediol expressed by the following formula: <CHEM> and (3R, 5R)-(+)-2,6-dimethyl-3,5-heptanediol expressed by the following formula: <CHEM> are disclosed, which are useful as reagent for asymmetric synthesis such as chiral auxiliary and chiral synthon.

Description

Description: FIELD OF THE INVENTION The present invention relates to a novel optically active compound useful as an asymmetric synthesis reagent such as a chiral auxiliary or a chiral synthon.

[Background of the Invention]

Optically active diols are extremely useful as various asymmetric synthesis reagents, for example, as an asymmetric source in the synthesis of optically active acetals, or as a chiral auxiliary for the diastereo-simmons-Smith-Smith reaction. Among the optically active diols generally used as asymmetric synthesis reaction reagents, the most typical one is 2,4-pentanediol (hereinafter abbreviated as PD). However, the optically active PD has a relatively low melting point of 50.5 ° C., and has a drawback that it is difficult to handle because it is extremely hygroscopic and difficult to dry, so there is a problem particularly when used in an anhydrous reaction. there were. Therefore, the appearance of a novel optically active diol which does not have such a problem and has excellent characteristics as an asymmetric synthesis reaction reagent has been desired.

[Object of the invention]

The present invention has been made in view of the circumstances as described above, has excellent properties as an asymmetric synthesis reaction reagent, has a melting point much higher than optically active PD, has no hygroscopicity, is easy to handle, and is anhydrous. It is an object of the present invention to provide a novel optically active diol that can be used for the reaction of

[Configuration of the invention]

The present invention uses the formula In shown (3 S, 5 S) - (-) - 2,6- dimethyl-3,5
- heptanediol (hereinafter, (3 S, 5 S) - (-) - DM
HD. ).

The present invention also relates to the formula (3R, 5R)-(+)-2,6-dimethyl-3,5-
It is an invention of heptanediol (hereinafter abbreviated as (3R, 5R)-(+)-DMHD).

The compound of the present invention can be easily synthesized by, for example, an enantioselective hydrogenation reaction of 2,6-dimethyl-3,5-heptanedione.

That is, for example (3 S, 5 S) - (-) - case of DMHD,
In an autoclave, 2,6-dimethyl-3,5-heptanedione and a suitable organic solvent (for example, tetrahydrofuran (TH
F), methyl propionate, ethyl acetate, etc.) and a small amount of acetic acid (or pivalonic acid, propionic acid, etc.), and Raney Ni modified with a mixture of (R, R) -tartaric acid and NaBr.
((R, R) -tartaric acid-NaBr-RNi), hydrogen was introduced, and the mixture was shaken (or stirred) at 80-120 kg / cm ² , 80-120 kg / cm ² .
C., preferably at 90-100.degree. C. for 2-10 days. After the reaction, the reaction mixture is cooled and hydrogen is allowed to evaporate, and then the mixture is filtered to remove insolubles and the solvent is distilled off from the liquid to give a colorless solid quantitatively. solvents (such as diethyl ether, diisopropyl ether, etc.) does not contain any racemic be 1 to several times recrystallized, (3 S, 5 S) - (-) - DMHD can be obtained as colorless needles.

Here, instead of (R, R) -tartaric acid-NaBr-RNi, (S,
S) - Using the tartaric -NaBr-RNi, (3 S, 5 S) -
Instead of (-)-DMHD, (3R, 5R)-(+)-DMHD is obtained in a similar manner.

The starting material 2,6-dimethyl-3,5-heptanedione is
For example, it can be easily obtained by Claisen condensation between methyl isobutyrate and methyl isopropyl ketone according to the method described in J. Am. Chem. Soc., 66 , 1220 (1944). May be used.

Also, (R, R)-(or (S, S)-) tartaric acid-NaBr-RN
i is obtained by adding Raney Ni catalyst to a modifying solution comprising (R, R)-(or (S, S)-) tartaric acid and NaBr according to the method described in Chem. Lett., 1978 , 1195, for example. It can be easily prepared by immersion at 100 ° C. for about 10 minutes to several hours. Therefore, it is sufficient to use one prepared in this way.

The compound of the present invention can be prepared by a method other than those described above, for example, BINA.
P (2,2'-bis (diphenylphosphino) -1,1'-dinaphthyl) -Ru (II) complex catalyzed asymmetric reduction of 2,6-dimethyl-3,5-heptanedione Of course, they can be synthesized.

Racemic and meso forms of 2,6-dimethyl-3,5-heptanediol have been described in various literatures and are already known, but are optically active 2,6-dimethyl-heptanediol.
3,5 heptane diol, i.e., (3 S, 5 S) - (-)
-DMHD and (3R, 5R)-(+)-DMHD have not been specifically described in literatures or the like. That is, the compound of the present invention has been synthesized for the first time by the present inventors, and its properties have been confirmed.

The compound of the present invention has a melting point of optically active PD of 50.5 ° C., which is slightly higher than room temperature, whereas its melting point is as high as 92 ° C., and the optically active PD has extremely high hygroscopicity and is difficult to dry. On the other hand, it is a smooth needle-like crystal, has no hygroscopicity, is easy to handle, and has properties far superior to optically active PD, such as when used quantitatively in an anhydrous reaction. In addition, unlike the optically active PD, the compound of the present invention has high fat solubility and can be easily recovered by a normal extraction operation (for example, when extracted with benzene, diethyl ether or the like, PD remains in an aqueous layer, but the compound of the present invention In that case, more than 95% is transferred to the oil reservoir.)

When the compound of the present invention is used, for example, as a chiral auxiliary in a diastereoselective reaction of a cyclohexene derivative by the Simmons-Smith reaction, the asymmetric yield when the optically active PD is used as the chiral auxiliary is up to 95%. However, it clearly increases to 99.8% or more. Thus also,
In the case of using optically active PD, selectivity is significantly affected by reaction conditions such as solvent and temperature, whereas in the case of the compound of the present invention, the effect of these reaction conditions is extremely small.

When the compound of the present invention was used as an asymmetric source in the following reaction, when optically active PD was used as an asymmetric source (R = C
The diastereomer ratio of the product [X] of H ₃ ) is 87:13 [Tet
rahedron Lett., 25 , 3947-3950 (1984)], whereas the compound of the present invention (R = isoC ₃ H ₇ ) has a significantly increased selectivity of> 99: <1.

(It is well known that the optically active alcohol can be easily obtained by oxidizing the product [X] according to a conventional method and treating it with a base.) As described above, the compounds of the present invention are greatly expected to be used for improving reactions using optically active PD or as chiral synthons for reactions where optically active PD could not be used. Further, the compound incorporating the compound of the present invention exhibits almost the same optical behavior as the compound incorporating the optically active PD, and thus is already known. The usefulness of the compound of the present invention is also recognized in that it can be used in various asymmetric synthesis reactions using optically active PD in the same manner as in the case of optically active PD.

Examples and Reference Examples are shown below, but the present invention is not limited by these Examples and Reference Examples.

〔Example〕

Reference Example 1. Synthesis of 2,6-dimethyl-3,5-heptanedione In a nitrogen stream, 83 g of sodium amide was added to anhydrous diethyl ether 1, and 183 g of 3-methyl-2-butanone was added to 180 ml of anhydrous diethyl ether with stirring. The solution was added dropwise over 10 minutes. After stirring for 5 minutes, add methyl isobutyrate 21
A solution of 7 g of 180 ml of anhydrous diethyl ether was added, and the mixture was further stirred for 2 hours. After the reaction, the reaction solution was neutralized with N-HCl,
And diethyl ether 1 was added for extraction. The ether layer was concentrated and the resulting residue was purified by repeated distillation to give 2,6-dimethyl-3,5-heptanedione 11
0 g was obtained. Yield 33.1% bp 85-87 ° C / 35mmHg.

Reference Example 2. Preparation of (R, R) -tartaric acid-NaBr-RNi (1) Preparation of modified solution (R, R)-(+)-Tartaric acid 20 g and NaBr 200 g were dissolved in deionized water 2 and the pH of the solution was adjusted. Was adjusted to 3.2 with N-NaOH.

(2) Preparation of Raney Ni catalyst 90 g of NaOH was dissolved in 400 ml of deionized water, and 38 g of a sufficiently pulverized Raney nickel alloy (Ni: Al = 42: 38) was added little by little over 15 minutes. Bring the resulting suspension to 100 ° C for 1
After keeping the time, the alkaline aqueous solution was removed by decantation, and the catalyst was washed 15 times with 500 ml of deionized water.

(3) Preparation of (R, R) -tartaric acid-NaBr-RNi 16 g of the Raney Ni catalyst obtained in (2) was immersed in the modified solution obtained in (1) at 100 ° C, and the container was shaken occasionally at the same temperature. After 1 hour, the solution portion was removed by decantation, and the residue was washed with deionized water. After repeating this operation again, the residue was sequentially washed with methanol and THF to obtain the desired (R, R) -tartaric acid-NaBr-RNi.

Reference Example 3. Preparation of (S, S) -tartaric acid-NaBr-RNi In Example 2, (S, S)-(-)-tartaric acid was used instead of (R, R)-(+)-tartaric acid. (S, S) -tartaric acid-NaBr-RNi was obtained in exactly the same manner as in Reference Example 2 except for the above.

Example 1. (3 S, 5 S) - (-) - Synthesis autoclave DMHD was obtained in Reference Example 1 2,6-Dimethyl -
102 g of 3,5-heptanedione, 220 ml of THF and 2 ml of acetic acid were charged, and (R, R) -tartaric acid-NaBr-RNi obtained in Reference Example 2 was added thereto.
(Prepared using 38 g of Raney nickel alloy), and introducing hydrogen to adjust the internal pressure to 100 kg / cm ^2.
The mixture was shaken for one week while keeping the temperature at 0 ° C. After the completion of the reaction, the system was cooled and hydrogen was allowed to evaporate, and the contents were taken out of the autoclave to remove insolubles. When a colorless solid solution was concentrated and the resulting three times recrystallized with diethyl ether 200ml (3 S, 5 S) - (-) - DMHD of colorless needles 31.4g was obtained. Yield 30.0%.

 m.p 91.5-92 ° C.

[Α] _D = -63.8 ゜ (C = 1.0, CH ₃ OH).

 Optical purity: 99% ↑ (by HPLC analysis).

Elemental _{analysis: C 9 H 20 O 2 =} 160.26 Found (%): C; 67.01, H; 12.59 theory (%): C; 67.45, H; 12.58.

_{^{1 H-NMR (CDCl 3)}} δppm: 3.66-3.62 (m, 2H, C H -O
H), 2.12 (d, J = 4.4 Hz, 2H.OH), 1.71 _{1.61-1.59 (m, 2H, CH 2} ), 0.96 (d, J = 6.8Hz, 6H, C
_{H 3), 0.91 (d,} J = 6.8Hz, 6H, CH 3).

IR (neat): 3360 cm ^-1 (OH), 2980 cm ^-1 , 2920 cm ^-1 , 1
410 cm ^-1 , 1390 cm ^-1 , 1040 cm ^-1 .

Incidentally, the absolute configuration of the compound was obtained by partially oxidizing the compound [A] ([α] _D = −50.4 °) and a compound derived from (S)-(−)-[B] whose absolute configuration was known [ A] was determined to be (3 S , 5 S ) from the coincidence of the optical rotation directions of [A].

Example 2 Synthesis of (3R, 5R)-(+)-DMHD In Example 1, (S, S) -tartaric acid-NaBr-RNi was substituted for (R, R) -tartaric acid-NaBr-RNi. Example 1 except used
The reaction and post-treatment are performed in exactly the same manner as (3R, 5R)
30.8 g of colorless needles of-(+)-DMHD was obtained. Yield 29.4
%.

 m.p. 912.5-92 ° C.

[Α] _D = 63.2 ゜ (C = 1.0, CH ₃ OH).

 Optical purity: 99% ↑ (by HPLC analysis).

¹ H-NMR and IR are the same as those of the compound obtained in Example 1.

Application example 1. Diastereo-discriminating Simmons-Smith reaction of cyclohexene derivatives Compound [II] is (3 S, 5 S) - (-) - DMHD and the presence of a cyclohexanone Toshirukorijin was obtained by refluxing the reaction in benzene (yield 87%) Compound [I] further CH Obtained by reacting with triisobutylaluminum at 0 ° C. in ₂ Cl ₂ / hexane solvent and working up with NaOH solution (98% yield).

333 mg of this compound [II] was dissolved in 10 ml of the solvent shown in Table 1, 7 ml of a 1 M hexane solution of diethyl zinc was added at the temperature shown in Table 1, and methylene iodide was added dropwise at the same temperature. The reaction was stirred for a certain period of time as described in 1. After the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction solution, the mixture was cooled, and the product was extracted with ether. The extract is concentrated and subjected to medium pressure chromatography using silica gel (MPL
C) to give a diastereomer mixture ([III] +
[IV]) 304 mg were obtained. Table 1 shows the results. The mixing ratio of diastereomers was determined by analyzing with ¹³ C-NMR and capillary GLC. Also, (1S, 6S)-(-)-1
Leading to bicyclo [4.1.0] heptanol,
It was confirmed that the compound present in a large amount was Compound [III].

* After reacting at -40 ° C for 0.5 hour, 1.5 hours
The temperature was raised to 0 ° C, and the reaction was further performed at 0 ° C for 0.5 hour.

Reference Example 4 In the application example 1, (3 S , 5 S )-(−)-DMHD is changed to (S,
A cyclohexene derivative was synthesized in exactly the same manner as in Application Example 1 except that S)-(−)-PD was used, and a diastereo-discriminating Simmons-Smith reaction was performed in exactly the same manner as in Example 1. Table 2 shows the results.

As is clear from Tables 1 and 2, the diastereoselectivity (de) of the diastereoselective Simmons-Smith reaction relating to the optically active PD differs greatly depending on the type of solvent and the reaction temperature, and in the best case (dimethoxyethane). Even in the case of a solvent), de remains at about 95%.

On the other hand, in the case of the diastereomerically differentiated Simmons-Smith reaction according to the compound of the present invention, de is 95% or more in any case regardless of the type of solvent and the reaction temperature,
Especially in the case of diethyl ether solvent, reaction temperature 20 ° C. d.
e. = 99.8% or more, indicating that a compound substantially free of compound [IV] is obtained.

Also, it can be seen that the chemical yield is generally higher in the case of the Simmons-Smith reaction relating to the compound of the present invention than in the case of the Simmons-Smith reaction relating to the optically active PD.

Application Examples 2 to 6. In Application Example 1, in the same manner as in Application Example 1, except that cyclopentanone, cycloheptanone, cyclooctanone, 4,4-dimethylcyclohexanone, or 3-pentanone was used instead of cyclohexane. And diastereomerically distinguished Simmons-Smith reaction (in diethyl ether solvent, 20 ° C, 1.5hr
Reaction), the diastereoselectivity (dc) was 99% or more in each case, and the yield was as high as 85 to 95%.

〔The invention's effect〕

As described above, the present invention provides a novel optically active diol which has a melting point much higher than that of optically active PD, has no hygroscopicity, is easy to handle, and can be used for an anhydrous reaction. When the compound of the present invention is used as an asymmetric synthesis reagent, 1) higher stereoselectivity than when optically active PD is used, 2) selectivity is affected by reaction conditions such as solvent and temperature It has a remarkable effect on points that are difficult to perform. Therefore, the compound of the present invention can be greatly expected to be used in the synthesis of various physiologically active compounds, such as for improving a reaction using an optically active PD as a chiral auxiliary or as a chiral synthon in a reaction where PD could not be used. Things.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 45/68 C07C 45/68 45/72 45/72 49/12 49/12 49/17 49/17 AE C07D 319/06 C07D 319/06 319/08 319/08 C07M 7:00 (56) Reference JP-A-63-316742 (JP, A) JP-B-60-14616 (JP, B2) Tetrahedron, 44 (13), p. 3761-3770 (1988) Chem. Soc, Chem. Commun. , 11. p. 831-832 (1986) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07C 31/20 C07B 53/00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] (1) Expression In shown (3 S, 5 S) - (-) - 2,6- dimethyl-3,5
-Heptanediol. (2) (3R, 5R)-(+)-2,6-dimethyl-3,5-
Heptanediol.